A daily regimen of the antibacterial drug trimethoprim-sulfamethoxazole (TS) reduces disease and death among people living with HIV in sub-Saharan Africa by preventing opportunistic infections including bacteremia, pneumonia and enteritis as well as malaria. It is not known whether this protective effect persists after immune reconstitution in HIV-infected persons receiving antiretroviral therapy (ART) or if infections prevented by TS, including malaria, influence the progression of HIV disease. With the scaling up of ART in Africa, public health authorities need to know if TS prophylaxis is necessary for those who are stable on ART. ART is associated with a dramatically reduced risk of typical AIDS-associated opportunistic infections. We therefore hypothesize that if there is a benefit of TS prophylaxis after immune reconstitution in this setting it will be due to the prevention of malaria infection, and that prophylaxis with a highly efficacious antimalarial drug (chloroquine, which now has 99% efficacy against malaria in Malawi) will be superior to daily prophylaxis with an antibacterial drug with lower antimalarial efficacy (TS, which had 80% efficacy against malaria in recent studies in Malawi). [unreadable] [unreadable] The overall public health objective of this application is to determine if TS can safely be stopped after immune reconstitution on ART. The primary research question is whether persons who are clinically stable on ART benefit from antibacterial prophylaxis, antimalarial prophylaxis, both, or neither. Secondary questions focus on understanding the role that antimicrobial prophylaxis may play in improving sustained responses to ART by preventing infections associated with rises in HIV viral load, and assessing antimalarial drug efficacy and selection for drug resistance in HIV-infected persons. To address these questions, we have designed a three-arm randomized open-label clinical trial comparing daily TS prophylaxis for prevention of malaria and bacterial infections, with weekly chloroquine prophylaxis to prevent only malaria, compared to no prophylaxis, in adults who are clinically stable after 6-12 months on ART. [unreadable] [unreadable] Under previous funding a protocol for this trial has been written and IRB approval obtained. This R34 will support completion of planning for the study and lead to submission of a U01 grant application to support the conduct of the clinical trial at the Blantyre Malaria Project Ndirande Research Clinic in Blantyre, Malawi. [unreadable] [unreadable] [unreadable]